Sutures having long-lasting biocidal properties

ABSTRACT

Surgical sutures having long-lasting biocidal properties comprising a suture strand having substantially uniformly incorporated therein a substantially water-insoluble salt of a basic antibiotic and cephalosporin.

United States Patent Kurtz 1 1 *July 29, 1975 [5 1 SUTURES HAVING LONG-LASTING 2,743,268 4/1956 Stieff 424/181 x BIOCIDAL PROPERTIES 2,751,910 6/1956 Howes 424/26 X 2,830,011 4/1958 Parker ct a1. 424/181 [75] Inventor: L onard urtz, Woodmere, 3,069,320 12/1962 Vitalis 424/181 3,235,556 12/1966 Wakeman ct 211...... 260/286 [73] Ashgnee' sutures Coventry Conn' 3,328,409 6/1967 Wakeman et al 260/286 1 Notice; The portion f the term f hi 3,388,704 6/1968 Kurtz 128/3355 patent subsequent to Feb. 15, 1989, has been disclaimed FOREIGN PATENTS OR APPLICATIONS 788,968 1/1958 United Kingdom 424/329 [22] F11ed: Apr. 25, 1972 pp No: 247,469 OTHER PUBLICATIONS The Merck Index, 8th Ed., Merck & C0., Inc., Rah- Appl'cam" Data way, N.J. JSA, pages 222, 485 & 848. [63] Continuation-impart of Ser. No. 648,247, June 23,

1967, abandoned, and a continuation-in-part of Ser. 5 739 Aug 20 19 9 abandoned, and a Primary ExaminerFreder1ck E. Waddell continuation-in-part of Ser. No. 243,425, April 12, Attorney, Agent, or Firm-Larson, Taylor and Hinds 1972.

52 11.5. C1 128/3355; 424/26 1 1 ABSTRACT [51 1 lift. C1 A611 17/00 Surgical sutures having g i g biocidal properties [58] Field 01 Search 424/26; 128/3355 comprising a suture Strand having Substantially formly incorporated therein a substantially water- [56] References C'ted insoIubIe salt of a basic antibiotic and cephalosporin.

UNITED STATES PATENTS 861,231 7/1907 Clark 424 26 )4 8 Drawmgs SUTURES HAVING LONG-LASTING BIOCIDAL PROPERTIES This is a continuation in part of my U.S. application Ser. No. 648.247, filed June 23, 1967 (now abandoned), U.S. application Ser. No. 851,739, filed Aug. 20, 1969, now abandoned and U.S. application Ser. No. 243,425, filed Apr. 12, 1972.

The present invention relates to sutures having longlasting anti-bacterial properties and to methods of providing such sutures.

There have been several attempts to provide antibacterial materials in sutures. For example, U.S. Pat. Nos. 861,231 and 2,751,910 relate to providing germicidal sutures. It is desirable that the bactericides should be tenaciously held by the suture to prevent rapid leaching and yet the bactericide cannot be so intimately held that its anti-bacterial activity is lost. The problem in the art has been to provide feasible techniques to make sutures with long-lasting anti-bacterial properties.

Sutures having long-lasting anti-bacterial properties are provided according to the invention by providing substantially uniformly throughout the body of the suture a substantially water-insoluble salt of a basic antibiotic and a cephalosporin. The bactericide is actually incorporated within the body of the suture strand and is not merely deposited on the surface thereof. The substantially water-insoluble anti-bacterial salts of the invention comprise a cation of a basic antibiotic and an anion of a cephalosporin and thereby provide a longlasting source of both a basic antibiotic effective against gram negative bacteria and a cephalosporin, an antibiotic known to be effective against gram positive bacteria. Thus, a persistent reservoir of a waterinsoluble agent is established within the suture which offers broad spectrum antibiotic activity against both gram negative and gram positive bacteria. In general, the solubility in water at 25C of the water-insoluble antibacterial salts of the invention does not exceed about 4.0 mg. per ml. and it is preferable to employ antibiotic salts whose solubility does not exceed 2.0 mg. per mil.

and still more preferable to utilize materials having asolubility of less than 1.0 mg. per ml.

Suitable antibiotics which may be used to form a substantially water-insoluble salt with the cephalosporins include basic antibiotics classified as polypeptides, sugars and bases. Among the polypeptides may be mentioned bacitracin, polymyxins, tyrothricin and vancomycin. Sugars include neomycin, erythromycin, strep-- tomycin and nystatin. Bases include cycloserine, tetracycline, aureomycin and terramycin. The preferred basic antibiotics are gentamicin and polymyxin B.

Illustrative of suitable cephalosporins are cephalolexin, cephaloglycin, cephaloridine and cephalothin.

Both the cation of the basic antibiotic and the anion of cephalosporin are conveniently provided in aqueous solutions of the respective antibiotics or their. watersoluble addition salts. Mineral acid salts of the basic antibiotic are particularly good sources for the cations whereas the alkali metal, e.g. Na and K salts of cephalosporinsare preferred sources for the anions. Prepara tion of the substantially water-insoluble salt is simply accomplished by combining these aqueous solutions of the cations and anions to form the salt which will precipitate.

. While the anti-bacterial materials are substantially insoluble in water, they are soluble in organic solvents and can be generally dissolved in good concentration in aqueous organic solvent solutions. The salts of gentamicin and cephalothin and the salt of polymyxin and cephalothin, for instance, are both soluble in methyl and ethyl alcohol, ether, ethyl acetate, benzene, chloroform, acetone, dime'thylsulfoxide and other common organic solvents. Thus, the anti-bacterial salts may be provided the sutures by dissolving the salt in a solvent which will swell the suture and the solvent plus the salt of the two antibiotic components will penetrate into thebody of the suture material. The solvent can then be removed by evaporation, extraction, etc. and the salt will remain incorporated in'the body of the suture.

Alternatively, the long-lasting substantially waterinsoluble anti-bacterial salts of the invention may be provided the suture by forming the salt as a precipitate in situ in the body of the suture. This may be accomplished by sequentially treating the suture with separate solutions containing the cation and the anion. If the solutions are aqueous, the precipitate is formed in situ. 1f the solutions are non'aqueous, the precipitate forms in situ when the suture makes contact with said nonaqueous solutions in an aqueous system.

In either of the methods described above for incorporating the salt, the solutions will include a swelling agent which enhances impregnation into the substrate. The swelling agent may be the water of the aqueous solutions or the solvent of the non-aqueous solution, or it may be an additional ingredient in either of these solutions. The solutions can be heated to aid impregnation provided that the anti-bacterial salt is not destroyed by such heat.

The invention is further illustrated in the examples which follow.

EXAMPLE 1 Twenty-five yards each of sizes 4/0, 2/0 and 2 surgical silk sutures are measured out and vacuum dried for 3 hours at F. The dry weight of each suture is taken and each suture is immersed in a 10% aqueous solution of gentamicin sulfate maintained at approximately 100F for about 8 to 24 hours. After this treatment the suture is removed from the oven and blotted to remove excess water. The sutures are then vacuum dried at 100F for 16 to 24 hours and their dry weight taken to determine the mg/yd pickup.

The resulting sutures are then each subjected to a second treatment comprising immersing the suture in a 10% aqueous solution of sodium cephalothin maintained at 100E for a period of 2-4 hours. The drying process described above is repeated and the mg/yd pickup is calculated.

The results of the above described treatments are set forth in the following Table 1.

Table 1 Sample No.

Antibiotic Gcntamicin Sulfate Gentamicin Sulfate 10% aq.

Gentamicin Sulfate Table 1 Continued Sample No. l 2 3 Suturc size 4/0 2/0 2.0 mg/yd. pickup 2 8.7 24.5 Antibiotic Sodium Ccphalothin Sodium Cephalothin Sodium Ccphalothin 10% aq. I071 aq. 10% aq. mg/yd. pickup 5.5 15.9 20.5 Total mg/yd. pickup 7.6 24.6 45.0

The aqueous solution employed in the above treat- 10 Table 3 ments are each capable of swelling the silk suture and an intra-fibrillar precipitate of gentamicin cephalothi- Sample 6 7 8 nate is thus formed well within the body of the suture. Suture Size M) u) The precipitate is then held tenaciously within the body lst treatment ni d of the suture such that it is very resistant to being disl Q 3348 l d ed b solvent action Si th 't' t b 0 y Q f P 'R e bu icku 8.6 17.6 36.1 stantially insoluble in water, it is highly resistant to the F y 14 7 ,7

I pic u .6 69.4 leaching actiori of body fluids and th s provides a per i 100 cc Hgo/min sistant reservoir for both the gentamicin and the cephafor 1 hr.) lothin antibiotics. It is also resistant to repeated washfinal/w" ings and thus provides sutures which are persistently effective against gram negative and gram positive bac- EXAMPLE Iv teria even after repe ed w hing Polymyxin B cephalothinate prepared as described in E am 1 lll is made u into the followin saturated so- EXAMPLE ii p e p g lution: The procedure of Example I is repeated substitut ng polymyximccphalmhin Complex 5 grams polymyxin B sulfate for gentamicin sulfate to provide DMSO (dimethylsulfoxidc) 25 grams a silk suture having incorporated therein polymyxin B 16 grams cephalothinate. The results of the treatments are Sum- Twenty-five yards each of sizes 2/0 and 2 braided Damariz d in the f ing 3O cron polyester (polyethylene terephthalate) surgical Table 2 Sample No. 3 4 5 Antibiotic Polymyxin B Sulfate Polymyxin B Sulfate Polymyxin B Sulfate lO'/z aq. 1071 aq. I071 aq. Suture size 4/0 2/0 2.0 mg/yd. pickup 2.3 10.6 24. Antibiotic Sodium Ccphalothin Sodium Ccphalothin Sodium Ccphalothin lO'lr aq. 10% aq. 107i aq. mg/yd. pickup 5.2 In 34. 7.5 26.9 58.

Total mg/yd. pickup EXAMPLE lll Polymyxin B cephalothinate 6 grams Ethyl alcohol grams Water 50 grams Twenty yards each of surgical silk sutures sizes 4/0,

-2/0 and 2 are predried in a vacuum oven at F for 3 hours. The dry weight of the sutures is determined and they are placed in the saturated solution of polymyxin B cephalothinate for 15 to 30 minutes. A platform is used to cover precipitate in the treating container in order to avoid surface crust on the suture. The. suture is then removed from the solution, the excess solution. blotted off and the suture vacuum dried for 16 to 24 hours at 100F. The pickup in mg/yd is determined on the dry suture and the process is repeated to give additional pickup. Multiple treatment of the silk sutures with this solution produced the following results:

sutures are predried and treated with this solution in the manner described in Example Ill. The results of the treatments are as follow:

The suture material can be natural, such as silk, gut and cotton, or synthetic such as regenerated cellulose, cellulose esters. polyamides such as nylon, polyacrylics, polyesters, polyglycolides, polylactitides, polyvinyls. polyolefins such as polyethylene and polypropylene and similar polymeric materials.

Preferred suture materials are nitrogeneous, organic, amphoteric filmor fiber-forming materials such as silk, gut or polyvinyl pyrollidone.

It has been found that the amphoteric nature of these materials effects an intimate bonding of cationic and anionic components of the water-insoluble antibiotic salts of the invention with the body of the suture during preparation of sutures of the invention. Thus, with sutures of nitrogenous, organic, amphoteric filmand fiber-forming materials not only are the substantially water-insoluble antibiotic salts held tenaciously within the body of the suture but this retentive characteristic is further enhanced by the bonding that occurs between the amphoteric material and the cations and anions of the basic and acid antibiotics. These enhanced bonding or retentive characteristics exhibited by the nitrogenous amphoteric materials is confirmed by the fact that substantially greater concentrations of basic and acid antibiotics can be introduced into the body of a suture fabricated from these materials compared to nonamphoteric materials.

vAs mentioned above, the substantially waterinsoluble antibiotic salts useful in the invention are not more soluble than about 4.0 mg per ml. Since there are a number of basic antibiotics to choose from the precipitate the salts of the invention, it is feasible to provide salts having a solubility of less than 0.1 mg per ml at 25C. Several of the germicide salts have virtually unmeasurable solubility in water. However, sutures provided with these salts exhibit long-lasting antibacterial activity. Therefore, it is considered appropriate to include within the meaning of substantially insoluble, those materials which have a solubility in water which ranges from substantially undetectable to about 4.0 mg per ml at 25C.

The amount of insoluble compound provided in the suture can vary widely and large amounts can be provided by repeating the impregnation process. Antibacterial activity is achieved with very small amounts of material. In general, the amount of antibacterial ma terial in the suture will depend upon the intended use, and in general, up to 25 or even 50 percent by weight based on the suture material is contemplated. The minimum amount of bactericide is largely a matter of choice, but trace amounts and amounts as low as 0.1 percent by weight, based on the weight of the suture, are effective. Although more anti-bacterial material can be provided in some cases, it is generally not practical to do so since lesser amounts achieve the desired persistent anti-bacterial action and the preferred amount of anti-bacterial material for sutures is therefore between 0.1 and percent by weight based on the weight of the suture material.

The persistent biocidal activity of sutures provided with insoluble bactericide salts according to the invention is demonstrated by placing sutures prepared according to the invention as shown in the foregoing examples, in contact with a gram positive bacteria such as staphlococci and a gram negative bacteria such as Escherichia coli. Even after repeated washings, the area around a silk suture containing, for example, gentamicin cephalothinate or polymyxin B cephalothinate will remain clear of both organisms. Similarly, the persistent biocidal nature of the suture is illustrated by in vitro testings in mice. Silk sutures treated according to the invention, for example, with gentamicin cephalothinate or polymyxin B cephalothinate, after being implanted in mice for several days, show no growth of organisms when removed and placed in a culture medium.

The sutures to which the invention relates are, with the exception of the long-lasting germicide incorporated therein, of conventional configuration and materials. The sutures are generally sterilized and may be attached to suture needles in the usual manner and packages in a sterile condition.

It is claimed:

1. A surgical suture having long-lasting bactericidal properties comprising a suture strand having incorporated substantially uniformly within the body thereof throughout its length an effective amount of a substantially water-insoluble salt of a cephalosporin and a basic antibiotic selected from the group consisting of gentamicin and a polymyxin, said substantially waterinsoluble salt being held tenaciously in said suture strand to provide a long-lasting source of both said antibiotics.

2. The surgical suture of claim 1 wherein the basic antibiotic is gentamicin.

3. The surgical suture of claim 1 wherein the basic antibiotic is a polymyxin.

4. The surgical suture of claim 3 wherein the polymyxin is polymyzin B.

5. The surgical suture of claim 1 wherein the cephalosporin is cephalothin.

6. The surgical suture of claim 5 wherein said substantially water-insoluble salt is gentamicin cephalothinate.

7. The surgical suture of claim 1 wherein the said substantially water-insoluble salt is a salt of a polymyxin and cephalothin.

8. The surgical suture of claim 7 wherein the salt is polymyxin B cephalothinate. 

1. A SURGICAL SUTURE HAVING LONG-LASTING BACTERICIDAL PROPERTIES COMPRISING A SUTURE STRAND HAVING INCORPORATED SUBSTANTIALLY UNIFORMLY WITHIN THE BODY THEREOF THROUGHOUT ITS LENGTH AN EFFECTIVE AMOUNT OF A SUBSTANTIALLY WATER-INSOLUBLE SALT OF A CEPHALOSPORIN AND A BASIC ANTIBIOTIC SELECTED FROM THE GROUP CONSISTING OF GENTAMICIN AND A POLYMYZIN, SAID SUBSTANTIALLY WATER-INSOLUBLE SALT BEING HELD TENACIOUSLY IN SAID SUTURE STRAND TO PROVIDE A LONG-LASTING SOURCE OF BOTH SAID ANTIBIOTICS.
 2. The surgical suture of claim 1 wherein the basic antibiotic is gentamicin.
 3. The surgical suture of claim 1 wherein the basic antibiotic is a polymyxin.
 4. The surgical suture of claim 3 wherein the polymyxin is polymyzin B.
 5. The surgical suture of claim 1 wherein the cephalosporin is cephalothin.
 6. The surgical suture of claim 5 wherein said substantially water-insoluble salt is gentamicin cephalothinate.
 7. The surgical suture of claim 25 wherein the said substantially water-insoluble salt is a salt of a polymyxin and cephalothin.
 8. The surgical suture of claim 7 wherein the salt is polymyxin B cephalothinate. 